DESCRIPTION (Applicant's Abstract): The repeated administration of the psychostimulant methamphetamine (MA) has been shown to produce neurotoxicity to dopaminergic nerve temminals. Although the exact mechanism of MA-induced neurotoxicity is unknown, it has been proposed that oxidative stress contributes to this process. The overall goal of this project is to demonstrate that in response to a neurotoxic regimen of MA, dopamine and glutamate interact within the striatum to promote the formation of hydroxyl free radicals, and that free radical-mediated cellular damage is involved in the long-term depletion of brain dopamine in the rat. The specific aims of the proposal are to: 1) determine the time and dose-dependency of MA-induced hydroxyl radical formation, 2) determine the role of glutamate in MA-induced hydroxyl radical formation, 3) determine whether MA-induced neurotoxicity is associated with a decrease in drug-induced locomotor activity/stereotypic behavior, and whether this behavioral deficit can be attenuated with antioxidants or free radical scavengers. Determination of 2,3-dihydroxybenzoic acid, which is formed from the interaction of salicylate and hydroxyl radicals, will be quantified as an index of hydroxyl radical formation and in vivo microdialysis will be utilized to assess MA-induced dopamine and glutamate release in the brain. An understanding of the mechanisms of MA-induced toxicity ultimately will assist in determining the risk to human health associated with psychostimulant drug abuse.